Molecular dynamics study for C154Y mutant of aldo-keto reductase 1C3

Abstract

Amyotrophic lateral sclerosis (ALS), one of intractable neurological diseases, occurs by progressive disorder of specific motor neurons. Although the pathogenic mechanism of ALS has not been elucidated, 5~10 % of all cases have family medical history, which is called as hereditary ALS. Recently, genome analysis for hereditary ALS revealed that aldo-keto reductase (AKR) 1C3 has a low-active variant, the C154Y mutation. AKR1C3 is a reductase metabolizing ketone and aldose using NADP as a coenzyme. Though the C154Y mutation is located at the α4 helix and away from the active site, the enzymatic activity for the C154Y variant decreased to nearly half of that for the wild type. In order to investigate the cause of the decreased activity in the C154Y mutant from the viewpoint of the structure, we performed molecular dynamics (MD) simulations for wild-type AKR1C3 and the C154Y mutant and analyzed these solution structures. As a result, α helix conformation was partially unfolded in the α3 helix of the C154Y mutant. Moreover, hydrogen bond network around NADP was weaker in the C154Y mutant compared with the wild type. This result suggested that the C154Y mutant could not stably bind with NADP and could not exhibit fully the enzymatic activity.